| Project/Area Number |
21K15478
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | University of Tsukuba |
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Principal Investigator |
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Completed (Fiscal Year 2023)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2022: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
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| Keywords | Clonal hematopoiesis / Colorectal cancer / TET2 / Colon cancer / Clonal Hematopoiesis / Tet2 / Melanoma |
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| Outline of Research at the Start |
Clonal hematopoiesis (CH) with adverse survival outcomes has been found in 24% of solid cancer patients. TET2 and SRSF2 mutations are commonly found in CH. We made a colon tumor model in the livers of Tet2KO and Srsf2 mutated mice to study the effect of CH immune cells on tumor cells and the cancer cell stage susceptible to these cells in a native tissue-relevant context.
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| Outline of Final Research Achievements |
Immune cells with somatic mutations (IMsm) are infiltrated into tumor tissues in cancer patients with clonal hematopoiesis (CH). To examine the roles of IMsm in colorectal liver metastasis (CLM), colon cancer organoid cells (CCOC) were transplanted into spleens of various Tet2 conditional knockout mice: VAVCre (Tet2 deletion in all blood cells), LysMCre (myeloid), CD19Cre (B), and CD4Cre (T). We found that CML tumor burden of VAVCre and CD4Cre were lower than those of control. Differentially expressed gene analysis for WTA and immunofluorescence staining showed that PDCD1, TIM3, TIGIT, and LAG3, encoding inhibitory receptors were repressed in CD8+ cells sorted from VAVCre and CD4Cre livers comparing to control. In conclusion, deficiency of Tet2 in hematopoietic cells led to decrease of exhausted CD8+ T cells and suppressed CLM.
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| Academic Significance and Societal Importance of the Research Achievements |
We clarified the roles of clonal hematopoiesis in a colorectal cancer (CRC) liver metastasis model which is native-relevant. Our findings may bring attention about CH in the prognosis and treatment of CRC in the era of precision medicine.
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